Romiplostim in chemotherapy‐induced thrombocytopenia: A review of the literature

Abstract Chemotherapy‐induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single‐arm cohort, 85% (44/52) of all romiplostim‐treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046–0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062–0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061–0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.


| INTRODUCTION
Thrombocytopenia can arise from insufficient platelet production, increased platelet destruction, and/or splenic sequestration, representing a range of disorders. 1,2xamples include autoimmune disease, bone marrow disorders (e.g., aplastic anemia), and hematologic disorders involving peripheral cytopenias, radiation, surgery, hematopoietic stem cell (HSC) transplantation, or drugs. 3Druginduced thrombocytopenias account for 20%-25% of all drug-related hematologic disorders. 4yelosuppression is a common adverse consequence of many anticancer therapies, particularly cytotoxic chemotherapy, and is also found with targeted therapies. 5,6he use of supportive care has facilitated more aggressive cancer treatment, aiming to reduce disease progression or achieve remission.Supportive care for chemotherapyinduced anemia and neutropenia includes red blood cell transfusions, erythropoietin-stimulating agents, granulocyte colony-stimulating factors, and antibiotic therapy when indicated.However, until recently, therapy for chemotherapy-induced thrombocytopenia (CIT) was limited to platelet transfusions and supportive care during severe, symptomatic nadirs; specifically, transfusions to conduct major invasive procedures for platelet counts of ≤50 × 10 9 /L and prophylactic transfusions for <10 × 10 9 /L. 7Chemotherapy dose delay or reduction until platelet counts recover is a common strategy for persistent CIT, 6 often interrupting treatment and possibly impacting outcomes.While CIT incidence varies with cancer type and regimen (solid tumors: 21.9%-64.2%,hematological tumors: 28%-87.2% 6,8,9), Grades 3-4 CIT is especially notable with hematologic cancers (≤45%, depending on cancer type/regimen) and solid tumors treated with platinum, gemcitabine, or anthracycline chemotherapy (Table 1). 9hrombocytopenia may be from a number of causes in cancer patients, including bone marrow infiltration, infection, radiation, and hematologic malignancy itself.This manuscript focuses only on management of CIT.
Thrombopoietin (TPO) is the primary growth factor for megakaryocyte proliferation, differentiation, and platelet production. 10The TPO receptor (MPL), found on HSCs, megakaryocytes, and platelets, is a homodimeric receptor encoded by the human myeloproliferative leukemia virus (mpl) gene. 10TPO-receptor agonists (TPO-RA) are a class of drugs that bind and activate the TPO receptor but do not contain the peptide sequence of TPO itself.There are currently four available TPO-RA.Romiplostim is a peptibody. 11Eltrombopag, avatrombopag, and lusutrombopag are small molecules. 11The current FDA approved indications for TPO-RA are: Romiplostim (immune thrombocytopenia (ITP) and acute radiation syndrome), eltrombopag (ITP, hepatitis C-associated thrombocytopenia, severe aplastic anemia), avatrombopag (ITP, periprocedural thrombocytopenia in chronic liver disease), and lusutrombopag (periprocedural thrombocytopenia in chronic liver disease). 11There have been multiple studies of TPO-RA for treatment of CIT 11,12 To-date, only studies with romiplostim have been positive. 11ere, we provide an overview of CIT and the evidence for use of romiplostim in CIT.

| Mechanisms of CIT
Platelets are produced by megakaryocytes in the bone marrow in response to TPO and consumed through physiologic and pathologic coagulation, apoptosis, and clearance by the spleen and/or liver. 19,20Bone marrow suppression leading to thrombocytopenia can be from direct effects on megakaryopoiesis, including platelet release, and/or indirect effects on the bone marrow microenvironment and hematopoietic regulators. 19,22rugs may decrease platelet counts by reducing platelet synthesis, preventing platelet release from megakaryocytes, or increasing platelet apoptosis, destruction, and clearance. 21hile mechanisms by which some anticancer agents lead to thrombocytopenia remain unclear, many pathways have been implicated (Figure 1).These include impairing megakaryocyte and platelet production by affecting DNA synthesis/repair (alkylating agents and platinum analogs), 22 apoptosis (anthracyclines via Bax, cytochrome c release, and caspase-3 21 ) and the platelet clock Bcl-x(L) (B-cell lymphoma 2 [Bcl-2] homology 3 [BH3] mimetic chemotherapy agent ABT-737). 1 Thrombocytopenia may also be mediated through direct effects on HSCs (TKIs) 5 and cytotoxic T-lymphocyte antigen-4 or programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) inhibitors. 23ther possible mechanisms include induction of plateletspecific immunoglobulin G autoantibodies (nivolumab), 17 lymphodepletion or cytokine release syndrome (CAR-T cells), 16 through nuclear factor kappa B (proteasome inhibitors), 24 and via p53 (HDAC inhibitors). 15

| Incidence of thrombocytopenia with other anticancer therapies
The use of targeted agents can cause thrombocytopenia to varying degrees.Grade 3 or 4 thrombocytopenia was higher with PARPi than conventional chemotherapy (meta-analysis: 22.8% versus 14.9%, relative risk 1.63, 95% CI: 1.06-2.52,p = 0.03). 25ICI treatment can result in immune-related thrombocytopenia in non-small cell lung cancer (NSCLC), 17 Hodgkin's lymphoma, 26 pancreatic cancer, 27 and renal cell carcinoma. 28Further, ITP has been identified as a rare (1.2%) but pertinent cause of treatment-related death with ICIs.PD-1 inhibitor monotherapy was associated with a 2% thrombocytopenia rate; PD-1/PD-L1 inhibitor with chemotherapy had 6% higher thrombocytopenia risk. 29

| CIT/clinically significant CIT
1][32] Specifically, NCCN Guidelines® note that "definitions used in several studies include thrombocytopenia (platelets <100,000/mcL) for ≥3 to 4 weeks following last chemotherapy administration and/or following delays in chemotherapy initiation related to thrombocytopenia." 33The threshold of <100 × 10 9 /L for CIT (vs.<150 × 10 9 /L) reflects when cancer patients are more likely to experience negative consequences from thrombocytopenia (i.e., dose delays, reductions, and discontinuation) and recurrence in future cycles.Key clinical platelet thresholds for clinically significant CIT include <50 × 10 9 /L (increased bleeding risk with trauma or surgery), 34 <30 × 10 9 /L (increased ecchymosis/ purpura), and <10 × 10 9 /L, which can necessitate prophylactic platelet transfusion. 7he Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is the standard grading scale for CIT (Table 2). 35Platelet nadir depth may worsen with subsequent chemotherapy cycles and increase bleeding risk, making CIT a risk to monitor throughout treatment.Platelet counts generally start to drop by Day 7, reach a nadir by Day 14, and then gradually return to baseline levels by Days 28-35. 1 Prolonged thrombocytopenia (≥4 weeks) has been observed in many solid tumor types. 32n a retrospective analysis of patients with hematologic or solid malignancy (n = 609), of 1262 chemotherapy cycles, 99 (8%) had a chemotherapy dose delay of ≥7 days and 209 (17%) had a chemotherapy dose reduction (i.e., a decrease ≥20% or discontinuation). 36Thrombocytopenia contributed to 70% of dose disruptions (delays/reductions) and in ~30% of the 70% cases was the sole cause. 36IT timing also has important implications. 37In nadir CIT, platelet counts fall in the middle of the chemotherapy cycle to as low as Grades 3 or 4, but then recover by the beginning of the next cycle.In persistent CIT, platelet counts do not recover adequately for the next scheduled chemotherapy cycle to be given on time at full dose.Alternatively, persistent CIT may be defined as inadequate platelet recovery after chemotherapy is held for 1 week or longer.The efficacy of potential CIT treatments may best be detected with persistent CIT, as nadir CIT can resolve by itself. 38

| CIT-associated chemotherapy dose delays and reductions
0][41][42][43] Dose delays due to CIT lasting ≥7 days have been seen in patients with advanced NSCLC (32%), breast cancer (33%), and ovarian cancer (44%); likewise, dose reductions of ≥15% were seen in patients with NSCLC (50%), breast cancer (49%), and ovarian cancer (48%). 39,40hanges in dosing can be quantified in terms of relative dose intensity (RDI), which is the percentage of delivered chemotherapy dose relative to the reference dose intensity for a specific regimen.Chemotherapy dose reduction or delay are two factors leading to reduced RDI.
Several studies have examined the consequences of reduced RDI.A retrospective study of patients with advanced NSCLC (N = 3866) demonstrated a significant association between dose delays of ≥7 days or an RDI <85% and decreased survival, though other causes contributed to decreased RDI. 40In a prospective trial in patients with HER2-negative advanced breast cancer, intermittent administration of chemotherapy was associated with a 38% increased mortality risk. 44Further, in a study of metastatic breast cancer, RDI <85% resulted in a significant decrease in overall survival (p = 0.0086). 41Likewise, in a retrospective study of ovarian cancer, RDI <85% was associated with a 71% increase in mortality. 45Overall, a systematic review of RDI in metastatic solid tumors showed that an RDI ≥85% improved progression-free survival and overall survival. 46Thus, while dose modifications may improve platelet counts, alteration of anticancer regimens can worsen survival outcomes for patients.

MANAGEMENT
The goal of CIT management is to have safe and effective interventions that avoid the need to decrease RDI. 30,36,39reserving RDI remains a key parameter in optimizing patient outcomes; minimizing decreased RDI is thus an important goal when administering chemotherapy.
T A B L E 2 Thrombocytopenia grades and clinical significance.

Grade
Platelet count (×10 Abbreviations: ADL, activities of daily living; LLN, lower limit of normal.
T A B L E 3 Modifications of planned chemotherapy.

Dose delay
For any given cycle, a ≥7day delay from the standard dosing schedule Dose reduction A ≥15% decrease in the chemotherapy dose in any given cycle relative to standard dosing

| Earlier-generation platelet growth factors
Several growth factors were explored but did not change the CIT management paradigm.Oprelvekin (recombinant IL-11, Neumega®) was approved by the United States Food and Drug Administration to treat CIT, but had modest clinical benefits and significant side effects, leading to it no longer being available. 37Initial experience with first-generation thrombopoietic agents, recombinant human TPO (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), was promising for CIT. 1 However, due to the development of neutralizing antibodies in some patients receiving PEG-rHuMGDF that cross-reacted with endogenous TPO and resulted in thrombocytopenia, development of these agents was discontinued.The exception is rhTPO, available in the People's Republic of China for the treatment of ITP and CIT. 37A systematic literature review and meta-analysis showed benefit from first-and second-generation TPO-RAs used to treat or prevent CIT. 479][50] Eltrombopag must be taken without a meal or with a meal low in calcium (≤50 mg) and at least 2 h before or 4 h after any medications or products containing polyvalent cations, such as antacids, calcium-rich food, and mineral supplements, 51 all of which can be challenging for patients receiving cancer therapy.In a phase 3 trial investigating the orally administered TPO-RA avatrombopag in patients with solid tumors and primarily nadir CIT, avatrombopag did not meet the composite primary endpoint (avoiding platelet transfusions, chemotherapy dose reductions of ≥15%, and chemotherapy dose delays of ≥4 days) possibly due to the unexpectedly high rates of platelet recovery in the placebo group. 38Avatrombopag raised platelet counts and was well tolerated, with a safety profile similar to placebo and no increased venous thromboembolism.These results emphasize the difference between nadir CIT and persistent CIT, and the potential for spontaneous recovery in nadir CIT (which, by definition, does not occur in persistent CIT).Further studies are needed to determine the benefits of thrombopoietic agents for CIT compared with the current management of platelet transfusions or treatment modifications.

| Romiplostim's mechanism of action, pharmacokinetics, and pharmacodynamics
The TPO-RA romiplostim is a peptibody consisting of four TPO-receptor binding domains linked to an Fc domain to increase half-life (Figure 2A) (as reviewed in 3,32 ).Romiplostim binding to the TPO receptor results in increased megakaryocyte growth and maturation (Figure 2B).After subcutaneous romiplostim administration, peak serum concentrations occur at a median of 14 h (range: 7-50 h), with a median half-life of 3.5 days (range: 1-34 days), 52 and platelet counts increase 4-9 days after administration, peaking on Days 12-16.While once-per-cycle romiplostim dosing did not show effects on platelet counts or chemotherapy dose in lymphoma or NSCLC, 53,54 multiple romiplostim CIT studies found weekly dosing important in maximizing efficacy (Table SS1).In a phase 2 randomized study of patients with solid tumors with platelet counts <100 × 10 9 /L for at least 4 weeks due to CIT, weekly romiplostim corrected the platelet count (≥100 × 10 9 /L) in 93% (14/15) of patients within 3 weeks as compared with 12.5% (1/8) of untreated patients (p < 0.001). 32Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks.Likewise, a comprehensive retrospective study of 173 patients with CIT (153 had solid tumors, 20 lymphomas or myelomas) showed that weekly romiplostim dosing was superior to intermittent intracycle dosing, with higher median platelet counts (143 × 10 9 /L vs. 106 × 10 9 /L, p < 0.001) and response rates (81% vs. 63%, p = 0.006) and correspondingly fewer chemotherapy dose reductions/delays (82 vs. 224 per 100 patient-years, p = 0.010) and fewer bleeding events (11 vs. 34 per 100 patient-years, p = 0.029). 30he same study showed a numerical reduction in venous thromboembolism with weekly dosing (7.1 vs. 20 per 100 patient-years, p = 0.25). 30In a retrospective analysis of patients with solid tumors, 59% (10/17) of patients with baseline platelet counts <100 × 10 9 /L achieved platelet counts ≥100 × 10 9 /L with a single romiplostim dose, with six more reaching that threshold after 2-12 weekly doses. 55Another retrospective analysis of weekly romiplostim found that platelet counts improved in all patients, reaching ≥100 × 10 9 /L in 19/20 patients. 56Lastly, weekly romiplostim was effective in facilitating weekly maintenance therapy with temozolomide in patients with glioblastoma. 57In all, studies in both solid and hematologic cancers support weekly romiplostim dosing in CIT.

| Evidence on romiplostim dose selection, titration, and timing
In studies in which romiplostim showed clinical benefit, 30,32,[55][56][57][58] weekly weight-based dosing was adjusted by platelet count.Typically, the target platelet count was 100 × 10 9 /L (often also the measure of response) as that allowed chemotherapy to resume and surgery to proceed as necessary. 30,32,55,56If platelet counts rose above 200 or 400 × 10 9 /L, a dose titration schema was specified to hold or decrease the dose accordingly.The starting dose was generally 1-3 mcg/kg, with an escalation of 1 mcg/kg each week.Specifically, in the phase 2 prospective randomized study, 32 dosing was initiated at 2 mcg/kg and increased by 1 mcg/kg for up to 3 weeks to target platelet counts ≥100 × 10 9 /L, with the mean doses required to achieve and maintain target platelet counts being 2.6 mcg/ kg and 3.3 mcg/kg, respectively.In follow-up of those receiving ≥1 year of romiplostim, the mean dose remained ~3-5 mcg/kg up to 3 years. 58Retrospective studies showed similar patterns, with dosing typically initiated at 1-3 mcg/ kg and adjusted to target platelet counts ≥100 × 10 9 /L; the resulting optimized dose was ~3 mcg/kg for both solid and hematological cancers. 30,34,55,56,59,60Based on both animal and clinical studies, administering romiplostim on the same day as chemotherapy is associated with comparable outcomes as administration on other days of the chemotherapy cycle.SS1).In the phase 2 study of F I G U R E 2 (A) Romiplostim structure.(B) Romiplostim signaling and platelet production.eTPO, endogenous thrombopoietin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TPO-R, thrombopoietin receptor.This figure was adapted from a review on romiplostim. 64atients with solid tumors, 85% (44/52) of patients resumed chemotherapy with maintenance romiplostim after CIT correction; only 6.8% of patients (3/44) experienced recurrent chemotherapy dose reduction/delay due to isolated CIT.32 When patients receiving romiplostim maintenance and chemotherapy were followed-up for ≥1 additional year, 70% (14/20) of patients had no further CIT, four had a single dose delay, and two required dose reductions.58 The mean romiplostim dose remained stable at 3-5 mcg/kg up to 3 years, indicating no loss of effect.10% (2/20) of patients had thrombotic events (one a deep vein thrombosis, one multiple tumor-related infarctions), an incidence expected for patients with metastatic disease.There was no clinical evidence of either bone marrow fibrosis or secondary hematologic malignancies.The cancer associated thrombosis rate was not increased compared with historical evidence in patients with metastatic cancer, undergoing chemotherapy.30,32,58 Overall, data from this study indicate that romiplostim shows promising efficacy without new safety concerns when given in either the short or long term to patients with CIT.32,58 Retrospective studies have also reported promising data for romiplostim in CIT (Supplemental Table S1).The aforementioned study of 173 patients receiving weekly or intracycle romiplostim dosing had overall findings of significantly raised median platelet counts vs. baseline (116 × 10 9 /L vs. 60 × 10 9 /L, p < 0.001) and a response rate of 71%.Further, bleeding rates were lesser than reported historically in similar CIT populations and venous thromboembolic events occurrence was as expected for this patient population.30 The vast majority of patients were able to avoid chemotherapy dose reductions/delays (79%) and platelet transfusions (89%). Ths study expanded upon earlier smaller retrospective analyses of CIT in romiplostim-treated patients with various solid tumor types (n = 20).56 The large number of patients in the weekly/intracycle study allowed for multivariable logistic modeling of response to romiplostim in patients receiving various regimens (i.e., platins, taxanes, gemcitabine, fluorouracil, irinotecan, and temozolomide).Model results indicated that poor response to romiplostim could be predicted by tumor invasion of the bone marrow (odds ratio, 0.029, 95% CI: 0.0046-0.18,p < 0.001), prior pelvic irradiation (odds ratio, 0.078, 95% CI: 0.0062-0.98,p = 0.048), and prior temozolomide treatment (odds ratio, 0.24, 95% CI: 0.061-0.96,p = 0.043). 30Patients with these predictors of romiplostim non-response had considerably lower platelet counts and response rates of 23%, 20%, and 46%, respectively.Further, in an observational cohort study of 63 patients with CIT receiving romiplostim, 61 54/63 (86%) patients achieved a response (platelet count ≥75 × 10 9 /L and ≥30 × 10 9 /Lower baseline), with higher predicted response associated with lower baseline TPO levels (p = 0.036 in a generalized linear model).TPO levels <100 pg/mL predicted responses at ≥60% of platelet assessments in >90% of cases, whereas TPO levels >2000 pg/mL likewise predicted a lack of these responses in >90% of cases.

| CIT management guidelines
Current NCCN Guidelines for Hematopoietic Growth Factors indicate that possible use of romiplostim is a level 2A recommendation. 33The guidelines continue "The primary purpose of using TPO-RAs for CIT is to maintain dose schedule and intensity of chemotherapy when such benefit is thought to outweigh the potential risks." 33Further, the European Society for Medical Oncology supportive care guidelines in COVID note that "Thrombopoietin mimetics should be considered in patients with severe thrombocytopenia after chemotherapy." 62For romiplostim, the dosing strategy per National Comprehensive Cancer Network® (NCCN®) "includes weekly dosing beginning at 2-4 mcg/kg, increased no more than 1-2 mcg/kg per week, to target platelet count of 100,000-150,000/mcL." 33,63 Of note, per the prescribing information, the maximum dose of romiplostim for ITP is 10 mcg/kg weekly. 52The NCCN Guidelines further describe data for avatrombopag, eltrombopag, and lusutrombopag and state that "Insufficient data are available to support use of TPO-RAs other than romiplostim for CIT outside of a clinical trial." 33Regarding the phase 3 trial of avatrombopag in 122 patients with solid tumors and severe CIT, while avatrombopag-treated patients did have somewhat higher platelet counts and treatment was deemed safe, this study did not meet its primary endpoint (a composite of avoiding platelet transfusions, chemotherapy dose reductions of ≥15%, and chemotherapy dose delays by ≥4 days). 38urrent International Society of Thrombosis and Hemostasis guidelines recommend participation in a clinical trial for CIT, but add, "If unable to enroll in a clinical trial, we suggest consideration of a TPO-RA in the setting of inadequate platelet recovery at day 1 of a chemotherapy cycle to avoid chemotherapy dose reduction or a delay of ≥7 day assuming adequate neutrophil and hemoglobin recovery". 11

| FUTURE DIRECTIONS
There currently is no consensus definition for CIT, as platelet count thresholds typically vary from 50 to 100 × 10 9 /L.
There also is no standard nomenclature to describe the timing and persistence of thrombocytopenia.Establishing uniform terminology will help distinguish clinically relevant conditions, such as nadir vs. persistent CIT, which have clinical consequences.For clinicians wanting to treat CIT with romiplostim, predicting which patients would most benefit and refining the goal of therapy are of particular interest.There are data indicating that tumor invasion of the bone marrow, prior pelvic irradiation, prior temozolomide treatment, and higher baseline TPO levels are all predictors of non-response to romiplostim, however, prediction of response to romiplostim remains subject to ongoing study.The existing evidence indicates that the use of romiplostim in patients with CIT improves the ability to maintain full RDI of cancer therapy; however, whether cancer control is improved is yet to be demonstrated.These knowledge gaps should be considered in future clinical research and study design.

| CONCLUSIONS
Currently, there are limited options and no medical consensus regarding how to treat CIT to decrease bleeding and platelet transfusions and allow for optimal chemotherapy dosing.The development of the TPO-RAs as a possible treatment option has renewed interest in managing CIT, particularly with data expected soon from many trials for multiple agents, including phase 3 trials of romiplostim (NCT03362177 and NCT03937154).

3. 2 |
Second-generation platelet growth factors TPO-RAs are the second-generation thrombopoietic agents and a current focus of potential CIT treatments.

4. 2 |
Optimal romiplostim dosing in CIT 4.2.1 | Evidence on frequency of romiplostim dosing and associated efficacy

All grades by solid tumor type
9IT prevalence after chemotherapy by solid tumor type and chemotherapy regimen.9 T A B L E 1 35ading per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scale.35 Note: 3,30,32,59,60

4.3 | Clinical outcomes with romiplostim in CIT, response and safety
Available data indicate that romiplostim corrects CIT in most patients and that maintenance romiplostim allows for chemotherapy resumption and continuation without CIT recurrence (Table